Tumor lysis syndrome

In medicine (oncology and hematology), tumor lysis syndrome (TLS) is a group of metabolic complications that can occur after treatment of cancer, usually lymphomas and leukemias, and sometimes even without treatment. These complications are caused by the break-down products of dying cancer cells and include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure.

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Cause and risk factors

The most common tumors associated with this syndrome are poorly differentiated lymphomas, such as Burkitt's lymphoma, and leukemias, such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Other cancers have also been associated with TLS but are less common. Usually, the precipitating medication regimen includes combination chemotherapy, but those patients with lymphoma and ALL can be affected with steroid treatment alone.

Symptoms and pathogenesis

Hyperkalemia. Potassium is mainly an intracellular ion. High turnover of tumor cells leads to spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 7mmol/dL) [normal 3.5-5.0 mmol/dL] and they include

• severe muscle weakness or paralysis
• cardiac conduction abnormalities (can be fatal)

Hyperphosphatemia. Like potassium, phosphates are also predominantly intracellular. Hyperphosphatemia causes acute renal failure in tumor lysis syndrome, because of deposition of calcium phosphate crystals in the renal parenchyma.

Hypocalcemia. Because of the hyperphosphatemia, calcium is precipitated to form calcium phosphate, leading to hypocalcemia. Symptoms of hypocalcemia include (but are not limited to):

• tetany
• seizures
• mental retardation / dementia
• parkinsonian (extrapyramidal) movement disorders
• papilledema
• emotional instability / agitation / anxiety
• myopathy

Hyperuricemia. Uric acid is a breakdown product of DNA, converted by xanthine oxidase from xanthine and hypoxanthine, which are in turn purine breakdown products. Uric acid is more toxic to tissues than (hypo)xanthine. Uric acid nephropathy has been a dominant cause of acute renal failure but with the advent of allopurinol and uricase treatment, hyperphosphatemia has replaced this as the main cause of acute renal failure. Oddly, gout is not a feature of tumor lysis syndrome; the high uric acid levels that cause gout probably need to be present for an extended period of time before the putative crystals can develop.

Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute renal failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphomas and leukemias. The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleoprotein turnover but the tumor reuses the released phosphate for resynthesis of new tumor cells. In post-chemotherapy TLS, tumor cells are destroyed and no new tumor cells are being synthesized.

Diagnosis

TLS should be suspected in patients with large tumor burden who develop acute renal failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). (Most other acute renal failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL). Acute uric acid nephropathy is associated with little or no urine output. The urinalysis may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6-0.7 for most other causes of acute renal failure.

Cairo-Bishop Definition

• Laboratory tumor lysis syndrome: abnormalitiy in two or more of the following and occurs within 3 days before or 7 days after chemotherapy.
  • uric acid > 8 mg/dL or 25% increase
  • potassium > 6 meq/L or 25% increase
  • phosphate > 4.5 mg/dL or 25% increase
  • calcium < 7 mg/dL or 25% decrease
• Clinical tumor lysis syndrome: laboratory tumor lysis syndrome plus one or more of the following:
  • increase serum creatinine (1.5 times upper limit of normal)
  • cardiac arrhythmia or sudden death
  • seizure

A grading scale (0-5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.

Prevention

Patients about to receive chemotherapy for a cancer with high cell turnover rate, especially lymphomas and leukemias, should receive prophylactic oral or IV allopurinol (a xanthine oxidase inhibitor, which inhibits uric acid production) as well as adequate IV hydration to maintain a high urine output (> 2.5 L/day). Rasburicase (Uricase) is an alternative to allopurinol and is reserved for patients who are high-risk in developing TLS. It is a synthetic urate oxidase enzyme and acts by degrading uric acid. Alkalinization of the urine with acetazolamide or sodium bicarbonate is controversial. Routine alkalinization of urine above pH of 7.0 is not recommended. Alkalinization is also not required if uricase is used.

Treatment

Main articles: hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia

Treatment is first targeted at the specific metabolic disorder.

Acute renal failure prior to chemotherapy. Since the major cause of acute renal failure in this setting is uric acid build-up, therapy consists of rasburicase to wash out excessive uric acid crystals as well as a loop diuretic and fluids. Sodium bicarbonate should not be given at this time. If the patient does not respond, hemodialysis may be instituted, which is very efficient in removing uric acid, with plasma uric acid levels falling about 50% with each six hour treatment.

Acute renal failure after chemotherapy. The major cause of acute renal failure in this setting is hyperphosphatemia, and the main therapeutic means is hemodialysis. Forms of hemodialysis used include continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemofiltration (CVVH), or continuous venovenous hemodialysis (CVVHD).

References

• Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med 2004;116:546-54. PMID 15063817.
• Coiffier B, Mounier N, Bologna S, Ferme C, Tilly H, Sonet A, Christian B, Casasnovas O, Jourdan E, Belhadj K, Herbrecht R. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol 2003;21:4402-6. PMID 14581437.